Pyrazine derivatives and methods of preparing the same



Patented July 2 1 1 953 PYRAZINE :DERIVATIVES -A NDMETH o-esvorlraerlmmo THE SA E" V "HarryP;Da1alian,"Rutherford, N. J and Samuel y I W isliushner, Nanuet, N. Y.,'assignors.to American 7 Y .Cyanamid Company, New York,'N. Y.,=apcor 'poration of Maine invention relates ltd-new organic oom.- pounds. More particularly; :the-Jnvention relates to thiolpyrazinoateseand methods of-, preparing the same 1n the-past it 'f-known to prepare pyrazine m'onoearboxylie a'cidQand derivatives such as estera However, ing eneral, these compounds do not possess bacteriostatic 'or= bacteriocida1 properties. 1

'We have n'ow fourid that-the thiolpyrazinoates hereinafter described- -exliibit activity against acid-fast bacteria suchra s -tubercle bacillus. These compounds may be represented by the following structural fo'rmula:

inwhi'c'h Ris analkyl,*arylxaralkyl;*carba-lkoxy alkyl;thiocarbailkoxyorheterocyclie radicali I These compounds are, general, crystalline solids, however, in "some cases "they 'are*-'-liquid-.

They are generally soluble inthe *com monprganic solvents "such as-"petroleum "ether, a'cetonepether,

etc. They are "usually only slightly soluble or insoluble inwater; j 'Inp'repa'ring the-*compoundsof the presentc f f @Xe -Rf in which is hydrogen or an "alkali metal =or a heavy metal-enemas lead and R is as defined hereinbefore. I

The first intermediate used 'in' theprocess --of the present invention- "pyrazinoylchloride; a

known compound. It is preferred that this compound be freshly prepared *s-inee'it'has 1 a tendency to decompose :on standing. This intermediate is usually prepared by heating pyrazinoic acid with 'thionyl ohlorid'e -and distilling oil the desired acid schloriderla-fter removing the EXCESS iunrea'cted-thionyl chloride.

The mercaptansused as the secondgi-ntermediate inthe. present reaction are, in :generahknown compounds. The. alkylamercaptanszmay. bethose having alkylegroups. such :asmethylgethylapropyl, butyL. amyl, decyl, :etc. Theysmayralso :beemetal derivativesr'such .:as dead methyl; mercaptide, lead ention we react jrpyrazinoy'l-chloridewith a mer-' i'ioiaimsl toilette-256$ I ethyl *rnercaptidefllead n-propyl mercaptide, "lead v butyl 'mercaptide; lead 1 amyl -mercaptide, --etc; Corresponding alkali metal compounds such'as 1 sodium derivativeswanbe used -in a similar manner. Furthermore, *themercaptans--can be oompounds 'such-a's, for'examp'l'e, =thiolphenol, para ehlorothiolphenol, *para brdnio'thiolphehol, *paray iodothiolph'enol, para-carboxythiolphenol or carboxy thiolphenols. The aralkyl-mercaptans such as-benzyl, phenethyl; phenpropyland 'th'e -lik e ean be used inithe-present reaction.

The process ofthepresent-{invention -is=ge erally icarried out in an organic ---solvent -suoh as ether, benzene, ethyl'aceta'te and the like. It

can,=however, be carried out by merely' mixirlg the intermediates. The reaction usually takes place'at room temperature, although the temperature may vary from about 20 to 120C. or higher, depending upon theparticular intermediates or solvent used.

The'reaction, when carried out at -ro'om temperature, is usually allowed. to stand overnight or longer. However, ifv higher temperatures are used, such as therefluxing temperatures of the solvents enumerated above, the reactionmay be complete in a matter of one-'halfjhouri V 'O 'n" completion ,of the reaction the"cruderre action product is usually purified by'treatment with activated charcoal and distilled/ The product can be further-purified in the case of solidsby crystallization from-organic solvents 30; gms. {of lead,methylmercaptideje;grns.:iof pyrazlnoyl chloride (freshly prepared) and .5300

I, was dried, treated with activated chra'coal and hol, absolute alcohol andether.

grams of freshly preparedfpyrazinoylchlor 'At first, the suspensionwas-yellowish brown and with anhydrous magnesium sulfate and treated 2,646,431 'a-"irii- 3 4 ml. of dry ether were all stirred together overproducts 27 and 13 gms. were distilled together night, at room temperature. The ether was deunder reduced pressure. The fraction distilling canted off and the residue was extracted three at 155 to 180 C. was a colorless liquid with a times with 100 ml. portions of dry ether. The mercaptan odor. The liquid on analysis was nether solutionwas cooled in an ice-bath and 5 propylthiolpyrazinoate.

then washed twice with 200 m1. of ice coldsodium hydroxide solution. The ether solution E PLE 4 n-Propylthiolpyrazinoate then Qfi. 1:118 residug was brown 7 The n propylthiolpyrazinoate of Example 3 was liquid which crystallized out uponcoohng. Crude 10 a preparediimthe fl rm y m r 5 g of dark brown crytalsg It Was of freshly prepared pyra'zin'oyl'chloridetvith lead purified twice from acetone and crystallized from mpmpylmercaptide by Stirring Overnight In hot alcohol sintered 610-650 Clmelting Point the reaction benzene was used as a solvent and 5 Partly S0111b1e in PP Q m h ll .the procedure was the same as that of Example (20 Water Soluble m acetone} 95% 9 0- 1 3. A yield of gms. of crude n-propylthiolpyrazinoate as a brown liquid was obtained.

Phem lthmlpyrazinocte V Ethylthiolpyriiziiiodte- Toabout 300 ml. of dry ether was add 13 2o 19 gms. offreshlyprepared pyrazinoyl chloride and 15 gms. of thiolphenol were added to 300 ml.

v I e of dry benzene and refluxed for a half hour. The lead ethylmercaptide was adedd. After5the=.ad-., benzene was decanted fi and the residue was dition or lead ethylmercaptide was completed, the extracted three times w 5 1 of hot h wa ake by machine or abo five o r zene. The. benzene solution was treatedwithactivated charcoal, driedand; finallydistilledpfi. The residue was .29 gmsooicrude dark liquid. Upon cooling it crystallized out. It was purified twice from hot acetone ,and from hot ,ethanol.

and then, while swirling the flask, 23 gra'ih's' 0 later it changedto purplish red. The contents of the flask was filtered andwashed several times with dry ether, The ether insoluble portion was discardgd. The filtrate (ether. 50111131011) was 30 The product was further lcrystauized irom washed twice with 200 ml. of 5% ice-cold sodium V hot acetone and gavecream-polored crystals hydroxide solution, The ether solution was dried which sintered at 145,-.150? C. The pure prod V uct was fairly soluble in acetone, benzene, partw o cm a l d. fil l d T th ly soluble in 96% alcohol, absolutealcohol, ether, was distilled Off and left about 8 gmsrf browninsoluble in petroleum ether mo -40) and water. colored liquid which had a very powerful mer- V I 11 captan odor. This liquid was then distilled under 3 L reduced pressure and the following fractions B enzy lthiolpyrdziflodte- T Separated: 7 L I 4U 12 gms. of freshly prepared pyrazinoyl chloride,

25 gms. of lead benzylmercaptide and 250 ml. of dry benzene were all refluxed together for three hours on the stream-bath. The benzene was decanted ofi and the residue extracted three times with 100 ml. portions of hot benzene. The ben- Pot Distilla- 100430 40-65 10 Colorless liquid, on.

. I oimempmn zene solution was cooled downjto about '10" 'C. 130-150 65-70 5 Do and then washed twice with 200 portions of 100408 P ice cold 5%, sodium hydroxide solution. The

V I I benzene solution wastreated withactivated car- Thethird (III) traction on analysis for carbon, 0 130 1 and dried and the benzene was then distilled hydrogen, nitrogen and sulfur was in agreement A d k brown llq h q with the theoretical values f orethylthiolpyrazweighed 22 gms. and had a strong mercaptan innate, Y odor. The product was distilled under reduced 4 pressure and fraction distilling at 190-2005.,re-

, tained. It was further' 'puriiied by dissolving it n-Propylthiolpymzinoate I in acetone, treating it with activated carbon, f eshl. re Med a'zmo I'm-bride concentrating 1t down,'add1ng 95% ethanol and wa s s u fs gerided in g nfls. of benz ene. This phlnmg m m lce'barth T 91737511315 lWe-re was kept at room temperature and to this was filtered ofi and dned' The punficatflon efi r slowly added 12.4 gms. (16 ml.) of n-propylmerw repeated and the benzylthmlpyra'zmoate captan dissolved in 100 m1. of dry benzene. This fifi g 35 me s i 3 55b-57. was stirred overnight. The benzene solution was pro o; gg so 3 f a e n e decanted ofi and the residue left in the flask was 3 er f y 5 r e n extracted three times with 50 ml. portions of 9 0 mso u e m en dry benzene. The benzene solution was treated EXAMPL .7 with activated charcoal and dried. It was next distilled off and a dark liquid remained, which h w lww m m 1 V Thirteen grams of pyrazinoyl' chloride were upon cooling had few crystals. These crystals I were filtered ofi. Crude yield was 27gms. of dark Susp d d n 100 1. o d yben ne and tothis liquid. These crystals were purified twice from mixture was added 16.1 g. of p-chlorothiolphenol.

The reaction mixture was refiuxed'2.0 hours and a dark-brown solution. resulted. The solution hot acetone. An aqueous solution has a pH of about 2. These crystals are pyrazinoic acid. An- 7 other batch of crude n-propylthiolpyrazinoate was dried over'anhydrous magnesium sulfate, was prepared by the above procedure and a crude treated with activated charcoal, filtered and then yield of 13 gms. was obtained. The two crude concentrated to a thick brown .oil.- This'oil was ionally ,dil illed under reduced pie using initially the steam cone as a 'source' of was, sublimed off, a free ifl'a'me was used to distill over 'the'j'p chlorophenylthiolpyrazinoatewhich boiled at *1-20l25' C.-/l mm. The product idified in d te r nd was; sr sta lt i d product from' benzene. The recrystall weighed 7:0' g ns-and melted at*l-20 Ethyl-s -pyrazz'noyl thioglycollate and tergall t iireact d qrethid h 2() grams of thioglycollic acid were added to Y 250 cc.'of absolute ethanol containing 1 cc. of concentrated sulfuricacid. This 'mixture was ,refiuxed on a steamconeovernight, then concentrated to dryness.

The residual light yellow oil was distilled at. room pressure and the fraction coming over at 155-160 C. was collected. 14.5 grams of a colorless oil was obtained.

The above 14.5 grams'of the ester in absolute ether. The truce y'i crystals was obtained. The r sea twice by assaying it in 9 then adding "an equal amount of' wa er; stir bymeans 'of an ice-bathto 10-15 0. Ten V grams of potassium ethyl xanthate recently prepared was added to the-suspension and the mixture stirred for three hours at 10? C. A brown solution and a granular precipitate resulted. .The

. solid substance was separated byfiltration and ethanol was added to a solution of --6.6 grams of t v sodium methoxide in absolute ethanol. *Agitation for minutes caused a clouding of the so-' lution and upon the complete evacuation of the ethanol under reduced pressure, 22.4 grams of the sodium derivative were obtained. 7

16 gms. of pyrazinoyl chloridewere prepared in the usual manner, by refluxing pyrazinoic acid in thionyl chloride for three hours and distilling off the acid chloride after getting rid of all the excess unreacted thionyl chloride. The pyrazinoyl chloride was suspended in ethyl acetate and added to the 22.4 gins. of the ethyl-s-sodio thioglycollate (prepared above) in ethy1 acetate. The resulting purple suspension was stirred overnight after a slight exothermic reaction had subsided. .The next morning, the solution was filtered, to remove the inorganic salts, and concentrated to dryness. The product was a mixture of a yellow solid and a deep red oil. Upon the addition of a small amount of ethanol, the oil went into solution and the solid was filtered off. The solid was carefully washed with cold ethanol as it proved to be somewhat soluble in this medium. 4.3 grams of a yellow solid was collected which melted at 7l-'75 C. The filtrate was concentrated to dryness and the residual oil was distilled under reduced pressure. A solid which vaporized and solidified in the receiving flask at 120-200 C./l8 mm. pressure was collected, whereas, the material in the distilling flask decomposed completely. The solid proved to be a further amount of the desried product as shown by a mix-melt determination. 4.0 grams of the distillate'was collected and pooled with the filtered product. Recrystallization from ethanol lowered the melting point to 65-68 C., and gave a fine colorless crystalline product which on analysis was in close agreement with 'the theoretical values for ethyl-s-pyrazinoyl thioglycollate.

EXAMPLE 9 o-Carboxyphenylthiolpyrazinoate 21 gms. of freshly prepared pyrazinoyl chloride, 23 gms. of thiosalicylic acid and 400 mls. of dry benzene were all added together in a one liter flask and refluxed for about 26 hours (overnight). The benzene solution was decanted off and the residue was extracted three times with'50 mls. portions of dry warm benzene. The benzene solution was next distilled off on the steam bath, the liquid left in the flask was cooled. The crystals 'the filtrate was treated with activated charcoal.

and dried over magnesium sulfate (anhydrous) The benzene was distilledfoff under reduced pressureat room, temperature and a yellow,

syrupy material remained whichTcrsytallized on standing. The yellow crystalline o-ethyl-spyrazinoyl xanthate melted at '65 67 .0., and weighed 8.0 grams, i I

' We claim:

1. Compounds having the general formula;

in which Ris a member of the group consisting of a lowerqalkyl, phe'nyl, monocarboxyphenyl,

monohalophenyl, benzyl and lower carboxyalkyl radical-s.

. A lower alkylthiopyrazinoate.

. Ethylthiolpyrazinoate.

. n-Propylthiolpyrazinoate.

. Phenylthiolpyrazinoate.

. Benzylthiolpyrazinoate.

. o-Carboxyphenylthiolpyrazinoate.

. A method of preparing compounds having in which R. is a member of the group consisting of lower alkyl, phenyl, monocarboxyphenyl, mono I halophenyl, benzyl and lower carboxyalkyl radie cals, which comprises reacting pyrazinoyl chlo-p' ride with a mercaptan having the formula:

. X-S-R wherein X is a member of the group consisting of hydrogen, alkali metal and lead radicals and R 1s as defined above and recovering said compound therefrom.

9. A method of preparing a lower alkylthiopyrazinoate which comprises reacting pyrazinoyl chloride with 'a lead lower alkylmercaptide and recovering said compound therefrom.

10. A 'method of preparing e'thylthiolpyrazinoate which comprises reacting pyrazinoyl chloride with lead ethylmercaptide and recovering said compound therefrom.

11. A method of preparing n-propylthiolewes;

10 Number A method of preparing o-carboxyhhe'nflthiomyrazihoate which comprises reacting pyrazinoyl chloride with thiosalioycli'cacicl endfrecovering said compound therefrom. 7 w HARRY P, DALALIAN.

V SAMUEL KUSHNER. I References Cited in the file of this pate it' UNITED STATES PATENTS Name Da te 2,149,279 Dalmer et a1. Mar. 7, 1939 

1. COMPOUNDS HAVING THE GENERAL FORMULA:
 8. A METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA: 